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Down-Regulation of c-Met Inhibits Growth in the Liver of Human Colorectal Carcinoma Cells¹

Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [M. H. H., O. S., N. R., N. U. P., R. R., L. M. E., G. E. G.]; The Program in Cancer Biology, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030 [M. H. H, R. R., L. M. E., G. E. G.]; and The Johns Hopkins University School of Medicine, Kennedy Krieger Research Institute, Baltimore, Maryland 21205 [R. A., J. L.]

Overexpression of c-Met, the protein tyrosine kinase receptor for the hepatocyte growth factor/scatter factor, has been implicated in the progression and metastasis of human colorectal carcinoma. To examine the role of c-Met on in vitro and in vivo growth of human colon tumor cell lines, stable subclones of the high metastatic human colorectal carcinoma cell line, KM20, isolated from a Dukes’ D patient, with reduced c-Met expression were obtained after transfection with a c-Met-specific targeting ribozyme. The subclones were only modestly reduced in c-Met expression because of c-Met playing an important role in cellular survival. However, a 60–90% reduction in basal c-Met autophosphorylation and kinase activity were observed. Correlating with the reduction in c-Met kinase activity, subclones with reduced c-Met expression had significantly reduced in vitro growth rates and soft-agar colony-forming abilities. The in vivo growth of these cells was examined at both the ectopic SQ site and the orthotopic site of metastatic growth, the liver. SQ growth was delayed significantly in the c-Met down-regulated clones compared with controls, with tumors growing on loss of the ribozyme construct. In contrast, tumor incidence was significantly reduced when the c-Met down-regulated cells were grown in the orthotopic liver site. Thus, c-Met activation may be important in metastatic growth of colon tumor cells in the liver. Collectively these data demonstrate that a small reduction in c-Met protein levels leads to profound biological effects, and potential c-Met inhibitors may be of therapeutic value in treatment of colon cancer.

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